During desensitization of beta-adrenergic receptors in frog erythrocytes, the binding sites of this receptor are internalized. Certain classes of gangliosides were found to diminish the internalization of beta-receptor recognition sites. These effects can be attributed to the inhibition of the agonist binding to membrane-bound beta-receptors, thereby inhibiting the isoproterenol (IP)-sensitive adenylate cyclase. Methylamine and several other inhibitors of transglutaminase prevented the beta-receptor internalization and the loss of membrane-bound beta-receptors elicited by incubation with IP. The potency of these compounds to inhibit the internalization and desensitization of beta-receptors could be correlated with their potency to inhibit the Transgluatminase activity in the erythrocyte lysate. Thus, transglutaminase might be essential in triggering the internalization following IP binding to cell surface receptors. Various lysosomal enzymes can be detected in the lysate of frog erythrocytes. Lysosomotropic drugs caused a dose and time dependent decrease in the number of soluble beta-receptors in IP-treated cells. Our results suggest that beta-receptor recognition sites may be internalized in coated vescicles and solubilized by limited hydrolysis with lysosonal enzymes.